Prostate cancer is the most commonly diagnosed malignancy in American men, resulting in over 30,000 deaths annually. This high rate of mortality results mainly from the inability of standard therapies to effectively treat the metastatic form of the disease. Immune-based therapies represent a promising new approach to treating prostate cancer in part because the possible development of autoimmunity against non-malignant tissue (a potential side effect for most immune-based therapies) would not be problematic because the prostate is a non-essential organ. Several parameters can influence the efficacy of T cell-based therapies to treat cancer, one of the most critical being the development of tolerance towards the targeted tumor-antigens. To study the relationship between prostate cancer and T cell tolerance, we have developed a novel transgenic mouse system in which we can examine the functional status of a clonotypic population of CD4 cells specific for a prostate epithelial antigen in a variety of settings: 1) in the absence of disease, 2) during the development of prostate cancer, and 3) following androgen-ablation (a standard treatment for prostate cancer). Our preliminary data indicates that while prostate epithelial-specific CD4 cells are normally ignorant of their cognate antigen, the development of advanced prostate cancer converts this passive form of tolerance into a more active one in which these T cells are rendered functionally non-responsive. Interestingly, androgen-ablation mitigates the tolerogenic potential of prostate tumors, presumably by reducing the overall levels of tolerogenic antigen presentation, and potentially creating a therapeutic window during which tolerance might be less of an impediment towards tumor immunity. In this proposal we will investigate in more detail the relationship between prostate tumorigenesis and T cell tolerance by determining the disease stage at which tolerance develops, as well as the mechanisms by which tolerance is induced. Furthermore, we will apply this knowledge to the design of vaccine strategies to treat prostate cancer in a variety of therapeutic settings (including following androgen-ablation).